The immediate goal of the candidate, Tracy Lynne Lehman, DVM, is completion of a mentored program investigating retrovirus immunoregulation and pathogenesis, culminating in a PhD degree and development towards an independent research career. Dr. Lehman's long-term goal is to become a principal investigator conducting research on immunomodulatory strategies against diseases of animals and humans. The research training program will be centered in the Feline Retrovirus Research Laboratory directed by sponsor Dr. Edward A. Hoover at Colorado State University. The laboratory has a strong record of extramural funding and medical scientist training. The candidate's training plan involves laboratory and didactic instruction in contemporary cellular and immunological virology research methods applied to an animal model of retroviral immunodeficiency. The proposed research examines the immune response to lentiviral infection using the feline immunodeficiency virus (FIV) model, specifically evaluating the effects of FIV on myeloid dendritic cells (mDCs). We will address three specific aims: (1) to determine the time course and mechanisms of altered bone marrow (BM)-derived mDC function in FIV-infected cats, (2) to determine whether ex vivo manipulation of BM-derived mDCs from FIV-infected cats can restore function and suppress viral replication in vitro, and (3) to determine the effects of FIV infection on autologous mDC therapy in FIV- infected cats. In Aim 1 we will determine how FIV infection affects BM-derived mDC function through evaluation of TLR ligand-induced cytokine, interferon regulatory factor, and transcriptional regulator production and activation of the mitogen activated protein kinases ERK and p38. In Aim 2 we will evaluate the effects of altering three immunoregulatory cytokines, IL-12, IL-10, and TGF-beta, and of blocking indoleamine 2,3-dioxygenase on DC function and viral replication in vitro. Then in Aim 3 we will investigate the effects of FIV on DCs in vivo. With these studies we hope to further our understanding of the host response to infection and evaluate methods of interfering with virus-induced immune impairment. The FIV model is ideal for the evaluation of such processes during the entire course of lentiviral infection and the application of laboratory results to therapeutic trials. This information could lead to the development of effective therapeutics for a variety of diseases, including human immunodeficiency virus infection in humans.